# IPTi for malaria: a promising intervention with likely room to scale

## Summary

Intermittent preventive treatment in infants (IPTi) for malaria provides preventive antimalarial medicine to children under 12 months old. It is among the most promising programs we’ve identified in our active pipeline of new interventions. Not only does IPTi appear to be highly effective at reducing clinical malaria, it’s also underutilized (more below), and the population it targets is especially vulnerable to malaria. That implies potential to open up large amounts of room for more funding if IPTi begins to be used more widely—our crude estimate is between $50 million and$200 million globally once it’s scaled—which is something we’re increasingly thinking about as we aim to direct $1 billion in cost-effective funding by 2025. In September 2021, we recommended a small grant to Malaria Consortium and PATH to assess the feasibility and cost-effectiveness of implementing IPTi at national scale in two countries. This grant was the result of an atypical process for us: because we don’t know of any organizations currently implementing IPTi, we issued a request for information to several charities that we thought might be good candidates to do so (more below). We’re hopeful that this scoping exercise will answer some of our many open questions about IPTi, and that this intervention continues to look promising as we learn more. ## What is IPTi? Intermittent preventive treatment in infants (IPTi) for malaria is a program that distributes preventive antimalarial medicine (usually sulfadoxine-pyrimethamine, or SP) to infants, regardless of whether they have malaria, during routine immunization services. A Cochrane meta-analysis of 12 randomized controlled trials (RCTs) found that IPTi reduced cases of clinical malaria by 30%.[1] IPTi appears effective enough that the World Health Organization (WHO) began recommending it 12 years ago, in 2010.[2] However, our research has identified only one country, Sierra Leone, that has integrated IPTi into its routine national health care practice.[3] We think this neglectedness is due in part to potentially surmountable logistical factors, such as the need to coordinate work between national malaria control programs and national immunization programs.[4] Other barriers to implementation have included the way WHO guidelines identified which settings are appropriate for IPTi[5] (though we understand from speaking with other organizations in the malaria space that these guidelines are currently under revision), and challenges with administering previously available formulations of SP.[6] ## Why we’re excited about it • Effectiveness – If the results found by the meta-analysis were mirrored in real-world application, IPTi could be another powerful tool through which to reduce incidence of malaria, which continues to be one of the most deadly diseases among under-five children in sub-Saharan Africa.[7] • Room for more funding – With only one country having adopted IPTi, there are currently no charities and no philanthropic funding that we know of supporting its implementation at significant scale. The lack of investment in this intervention indicates that it measures up well on one of the criteria we use to assess programs: room for more funding. If IPTi begins to be used at scale in more countries, implementing organizations will likely be able to absorb a great deal of additional resources. • Cost-effectiveness – Our preliminary estimate suggested that IPTi may be around 18 times as cost-effective as cash transfers, which is above the range of cost-effectiveness of programs we would consider funding.[8] However, this estimate is quite rough, given our uncertainties about program costs, feasibility of implementation at scale, and the counterfactual impact of funding we might direct to IPTi. More below. ## What we’ve done so far In August 2020, we published an intervention report on IPTi, noting its efficacy in trials and our plans to explore funding opportunities. Normally, once we’ve identified a sufficiently promising intervention, our next step is speaking to the organizations running the programs that get it out into the world. This was an unusual case: because we know of no organizations implementing IPTi programs at substantial scale,[9] we issued a request for information (RFI) from several charities that we thought might be good candidates to implement the program, asking them how they would support governments that wanted to administer IPTi at scale. ### The RFI process and scoping grant The RFI asked applicants to briefly describe how they would approach a hypothetical IPTi program, including what geographies they would focus on, key uncertainties they would prioritize resolving before scaling the program, and their vision of path to scale. Out of seven applicants, we selected two organizations that we thought had the greatest potential for success—PATH and Malaria Consortium—to collaborate on a “scoping study.”[10] The study will assess the feasibility and cost-effectiveness of integrating IPTi into national health policy in Nigeria and Democratic Republic of the Congo (DRC), two countries with a high malaria burden.[11] We recommended a grant of$120,000 to fund the study,[12] which is expected to take four to six months.

Our hope is that the information gathered by PATH and Malaria Consortium during this process will allow us to build out a more sophisticated and accurate cost-effectiveness analysis of IPTi, develop a better sense of where IPTi could be implemented most successfully, and ultimately make an informed decision about whether we should direct funding toward scaling the program.

This RFI process was an experiment—we won’t necessarily be doing this as a matter of course in similar situations without readily identifiable implementing organizations. In this case, we think the process helped us figure out a partnership between two organizations with complementary strengths and experience working together in the past. Additionally, we believe that findings from the scoping study (as well as any funding we might direct as a result) may catalyze interest in IPTi from other funders, other implementers, and other countries in the region.

## What we’ll do next

The scoping study is expected to be completed by the end of January 2022, after which we’ll conduct a full investigation and build a cost-effectiveness estimate.

If IPTi still looks like a good use of funds after this stage, we’ll likely recommend an operational research grant to PATH and Malaria Consortium to implement IPTi at a smaller scale. This would be an opportunity to observe what IPTi implementation looks like in practice, learn, and make adjustments to the implementation plan as needed.

If the results of smaller-scale implementation are positive, we expect that could open up as much as $50 million in room for more funding to support expanding IPTi to all subnational areas deemed appropriate for the intervention.[13] ## Major uncertainties As IPTi has yet to be carried out at scale in most countries, we have a number of open questions about how effective and cost-effective it will turn out to be, though we’re hopeful that the scoping activities will go some way toward answering these questions. Uncertainties include: • Program costs – The technical assistance activities required to implement a program, such as health care worker training, monitoring, and drug procurement, can significantly increase total costs beyond the costs of the antimalarial medicines themselves. Our current estimate is that IPTi will cost about$4 per child treated, including all technical assistance costs,[14] but without documented evidence of spending to inform our guess, we have low confidence in this number. If IPTi turns out to be much more expensive than we guess now, it won’t be as cost-effective as we expect.
• Suitability and cost-effectiveness at the subnational level – During scoping, PATH and Malaria Consortium might find that some regions, states, or local government areas have a higher infant malaria burden than others, or have better coverage from insecticide-treated nets or seasonal malaria chemoprevention (SMC). Factors such as these could impact how large of an effect we’d expect to see from IPTi in those locations, which would in turn impact cost-effectiveness.
• Feasibility of implementing IPTi at scale – There are many setting-specific factors that contribute to whether IPTi implementation will be feasible or not, including level of interest from country decision-makers, strength of the supply chain that gets medicines where they’re needed, and quality of monitoring and evaluation systems. We expect all of these will become clearer to us when the scoping study is complete.
• Counterfactual impact of our funding – It might be that another funder would step in to support IPTi implementation in the next few years if we don’t, thus reducing the value of our funding recommendation.
• More specific questions around room for more funding – Although the absence of IPTi programs so far indicates likely room for more funding, this depends heavily on the uncertainties around suitability, feasibility, and cost-effectiveness we’ve listed above.

We also have some uncertainties around the scoping grant specifically, which we’ve described on the grant page.

## Why do we direct so much funding to malaria programs?

Two of our top charities, Malaria Consortium’s SMC program and Against Malaria Foundation (AMF), support interventions that protect against malaria, and we direct a lot of funding to them. In 2020, we directed over $60 million to AMF, and$69 million to Malaria Consortium for SMC, which together made up over half of our money moved.[15] If we were to begin to direct significant funding toward IPTi implementation while maintaining similar levels of funding for AMF and Malaria Consortium, that could weight our support even more heavily toward malaria interventions.

But we’re happy to invest heavily in fighting malaria, because:

• It remains a significant problem: malaria killed over 600,000 people in 2020, most of them children under five.[16] Though illness and death from malaria have been greatly reduced over the last several decades, that progress has slowed in recent years, and malaria deaths increased between 2019 and 2020.[17] The anti-malaria interventions we’re already supporting are inexpensive and highly effective,[18] and we intend to continue supporting them as long as both of those things remain true.
• There is no single tool that can effectively combat malaria everywhere. The success of an intervention can vary considerably from place to place, based on environmental factors such as insecticide or drug resistance among malaria parasites, or seasonal rainfall patterns and how malaria transmission is distributed throughout the year.[19] For this reason, some antimalarial measures can be used only in certain locations, some contraindicate each other,[20] and in many places a combination of multiple complementary tools is recommended.[21] We therefore see value in supporting a diversity of malaria prevention measures, which is why we’re also paying attention to new developments such as WHO’s recent recommendation of the RTS,S vaccine.
• There continues to be a lot of room for more funding in malaria prevention. In 2021, we directed $100 million to Malaria Consortium for SMC and another$97 million for insecticide-treated nets ($31 million to Malaria Consortium and$66 million to AMF).[22] We expect to identify at least a similar amount of room for more funding for these interventions in 2022. Our very rough calculations, based on countries that have expressed interest in IPTi or been proposed by organizations that responded to our RFI, suggest that the global funding gap for IPTi if scaled in suitable locations could be between $50 million and$200 million, depending on cost per child treated.[23]

## In conclusion

We’re tentatively excited by IPTi’s potential to reduce illness and death from malaria, but a lot of work remains to be done before we decide whether to recommend further funding. We expect to learn a lot from the scoping grant we’ve made to PATH and Malaria Consortium, and we’ll update when we have results from those activities. In the meantime, you can read more about IPTi in our intervention report, and more about the scoping grant on this grant page.

• ANGELO TOMEDI on February 6, 2022 at 9:34 am said:

It does seem like including infants in an IPT program is a promising additional intervention for malaria. However, the Cochrane review of the evidence doesn’t appear to be very convincing. Using SP for IPTi, there was no improvement in mortality or for severe malaria , and the effectiveness for clinical malaria prevention was not demonstrated in the most recent trials. This suggests the possibility of SP resistance limiting the effectiveness of IPTi with SP. This led the Cochrane reviewers to conclude: “On the basis of the more recently conducted trials that showed no effect of IPTi with SP, the prospects for the continued use of SP as IPTi are limited.” They also state that “There are a few trials that evaluated other drug combination options for use as IPTi with some evidence of effectiveness (Bigira 2014 UGA; Gosling 2009 TZA; Massaga 2003 TZA; Odhiambo 2010 KEN). However, larger adequately powered trials are needed to provide more robust evidence for or against IPTi.” Do you know if the scoping study to assess the feasibility and cost-effectiveness of integrating IPTi into national health policy in Nigeria and Democratic Republic of the Congo will be using SP?

• Miranda Kaplan on February 9, 2022 at 12:05 pm said:

Hi, Angelo – thanks for your thoughtful comment! You raise some very good points about SP resistance; we also have considered this a concern in our investigation of IPTi.

In answer to your final question, the scoping study discussed in the post, as well as any scaled-up program in DRC and Nigeria, will be using SP, because IPTi using SP (IPTi-SP, for short) has the most evidence behind it.

On the lack of effect on mortality, the trials in the Cochrane review were not adequately powered to detect such an effect, but we think reductions in clinical malaria probably translate to reductions in mortality (more in this section of our IPTi intervention report).

On SP resistance, studies suggest that IPTi-SP is effective in areas where SP resistance (meaning the prevalence of a genetic mutation in the malaria parasite that is a marker for resistance to SP) is up to 50%, but may be less effective where resistance is much higher. Experts we have spoken to generally agree that IPTi is likely still effective in areas with over 50% resistance, and implementation research to generate more evidence on this question is ongoing. There is also some indirect evidence (see WHO policy brief for IPTp-SP) that IPTp, or IPT of malaria for pregnant women, using SP remains effective in preventing malaria even in areas where fairly high levels of resistance make it ineffective at treating malaria.

The scoping study we are supporting is targeting areas where SP resistance is below 50%; in DRC, all the subnational areas chosen by the Ministry of Health for potential IPTi implementation have resistance levels below 25%. We have less data on SP resistance in Nigeria, but (1) a large-scale observational study, ACCESS-SMC, suggests that SP resistance in Nigeria is relatively low, and (2) integrating IPTi into routine health care practice in these countries would include assessments and monitoring of SP resistance at the subnational level, so the program could be targeted to areas where it will be most effective.

Additionally, Malaria Consortium is currently conducting a trial funded by the Gates Foundation to evaluate the effectiveness of IPTi in one or two Nigerian states. If we support scale-up of IPTi in DRC, we would consider including an impact evaluation component to assess its effectiveness there.

• William Kiely on April 25, 2022 at 12:51 am said:

Thanks for cross-posting this to the Effective Altruism Forum today. I hadn’t seen this post or any of GiveWell’s other posts related to IPTi before today, but was happy to see it and learn about GiveWell’s investigation of this intervention.

• Miranda Kaplan on April 25, 2022 at 10:03 am said:

Thank you, William!